New Research Suggests Previously Unrecognized
Mechanism by Which Blood Vessels Are PatternedUsing an Animal Model, Penn Researchers Identify Receptor in Endothelial
Cells
That Is Crucial for Cardiovascular Development

(Philadelphia, PA) – Congenital heart disease (CHD) is a leading
cause of mortality in children worldwide. According to the American Heart
Association, Congenital cardiovascular defects are present in about one
percent of live births and are the most common malformations in newborns.
Researchers from the University of Pennsylvania School of Medicine
have recently identified new signaling pathways that may lead to a better
understanding of how this deadly disease forms. Jonathan Epstein,
MD, Associate Professor of Medicine and the study’s lead
investigator, identified a receptor in endothelial cells (the cells that
line blood vessels) that when interrupted in mice, results in CHD and
defects in the growth and arrangement of blood vessels (patterning). “With
the identification of this receptor, we hope to one day develop molecular
medicines that will essentially steer developing blood vessels away from
where they shouldn’t go,” said Epstein.

This finding – published in the July 2004 issue of Developmental
Cell – may lay the groundwork for discovering ways to diagnose
and prevent CHD. In an accompanying article in Developmental Cell,
Epstein and collaborators at the National Institutes of Health demonstrated
the pathways that they have discovered are functional in diverse organisms,
including fish. In the larger picture, the researchers suggest this work
may be crucial in determining why blood vessels migrate to certain destinations
in the body.

The researchers engineered mice with an inactivated endothelial receptor,
called PlexinD1. These mice had structural cardiovascular defects involving
the outflow vessels of the heart, which resembled a common form of CHD
in children and caused perinatal deaths of PlexinD1 deficient mice.

The type of CHD caused by inactivation of PlexinD1 in mice has previously
been attributed to abnormalities of neural crest cells, which are important
in setting up the correct arrangement of tissue in a developing embryo.
“With this research, we have been able to show that this form of
CHD can be caused by defects within the cells that line blood vessels.
This research could lead to new ways to modify the growth of blood vessels
because this receptor seems to tell blood vessels in which direction they
should grow,” says Epstein. With this finding, researchers hope
to one day be able to manipulate where blood vessels go, which may lead
to the development of therapies for any disease in which the presence
of blood vessels is unwanted, including diabetic retinopathy and many
types of tumors.

Other Penn researchers contributing to this study are Aaron D. Gitler
and Min-Min Lu. This study was funded by grants from the National Institutes
of Health and the American Heart Association.

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PENN Medicine is a $2.5 billion enterprise dedicated
to the related missions of medical education, biomedical research, and
high-quality patient care. PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in 1765 as the nation’s
first medical school) and the University of Pennsylvania Health System
(created in 1993 as the nation’s first integrated academic health
system).

Penn’s School of Medicine is ranked #3 in the nation for receipt
of NIH research funds; and ranked #4 in the nation in U.S. News &
World Report’s most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students, the School
of Medicine is recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders of academic
medicine.

Penn Health System consists of four hospitals (including its flagship
Hospital of the University of Pennsylvania, consistently rated one of
the nation’s “Honor Roll” hospitals by U.S. News &
World Report), a faculty practice plan, a primary-care provider network,
three multispecialty satellite facilities, and home health care and hospice.